Vitreoretinal surgery has advanced in numerous directions during recent years. The removal of the vitreous body is one of the main characteristics of this surgical procedure. Several molecules have been tested in the past to fill the vitreous cavity and to mimic its functions. We here review the currently available vitreous substitutes, focusing on their molecular properties and functions, together with their adverse effects. Afterwards we describe the characteristics of the ideal vitreous substitute. The challenges facing every ophthalmology researcher are to reach a long-term intraocular permanence of vitreous substitute with total inertness of the molecule injected and the control of inflammatory reactions. We report new polymers with gelification characteristics and smart hydrogels representing the future of vitreoretinal surgery. Finally, we describe the current studies on vitreous regeneration and cell cultures to create new intraocular gels with optimal biocompatibility and rheological properties.

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<b><i>Purpose:</i></b> This study aimed to describe foveal microstructural changes after pars plana vitrectomy (PPV) with air tamponade for rhegmatogenous retinal detachment (RRD). <b><i>Methods:</i></b> External limiting membrane (ELM) and ellipsoid zone (EZ) integrity, cystoid macular edema (CME), and subretinal fluid bleb (SB) development were analyzed using optical coherence tomography in 59 eyes over a 6-month follow-up period after PPV surgery for RRD. Eyes were grouped as macula-on (<i>n</i> = 30) or macula-off (<i>n</i> = 29), and the association between ELM and EZ recovery and best-corrected visual acuity (BCVA) was investigated. Predictive factors for ELM and EZ recovery were also identified. <b><i>Results:</i></b> The interval between symptom onset and surgery did not significantly differ between the macula-on and macula-off groups. Macula-on patients showed ELM and EZ integrity throughout, whereas macula-off patients had ELM and EZ integrity restored in 89.7% and 86.2% cases, respectively, with a resultant increase in final BCVA. Significant associations were found between preoperative macular involvement and ELM/EZ restoration. ELM/EZ recovery was also inversely associated with CME development. Significant associations were also found between final BCVA and preoperative BCVA and EZ recovery. CME and SB development were equally distributed between the 2 groups. <b><i>Conclusion:</i></b> Prompt surgery for macula-off RRD allows the progressive recovery of outer retinal layers and significant visual gain.